Genotype and Rearing Several studies this year have investigated the role of the serotonin transporter genotype on the risk for high alcohol intake in the nonhuman primate as a model for Type II-like alcohol abuse. In last year?s report we indicated that, as in humans, a low level of response to alcohol is predictive of future excessive alcohol intake. In humans, studies have indicated that variation in the gene-linked polymorphic region of the serotonin transporter (5-HTTLPR) has been weakly associated with the level of response to the motor-impairing effects of alcohol. Dr. Christina Barr has performed similar analyses in the macaques, demonstrating an interaction between early rearing condition and serotonin transporter genotype, such that animals homozygous for the l allele exhibited lower levels of response to alcohol. When animals were segregated according to rearing condition, however, serotonin transporter gene variation predicted intoxication scores only among peer-reared (PR) subjects, suggesting that the risk for excessive alcohol intake and possibly alcoholism may be regulated in part by the interacting influences of early rearing and 5-HTTLPR genotypes. There is a high rate of co-morbidity of Type II alcoholism and antisocial personality disorder (ASPD). Studies of children with conduct disorder (often a precursor of ASPD) and retrospective reports of adult ASPD show that these individuals are particularly difficult to socialize. Play behavior is particularly important in the socialization of aggression, both in humans and in the developing macaque. Play behavior is a particularly important socializer of aggression in the developing macaque. Dr. Christina Barr?s studies of macaques as they develop reveal that PR infants with the 5-HTTLPR l/l genotype exhibit high rates of play as infants followed by low rates of aggression as juvenile. PR infants with the l/s genotype, on the other hand, exhibited low rates of play early in life, but show very high rates of aggression as juveniles. Mother-reared (MR) monkeys rates of play were undifferentiated by genotype, but for the MR monkeys, when the two genotypes were compared, the l/l MR subjects showed modestly higher rates of aggression as juveniles, possibly reflecting differences in the social milieu or underlying temperament of the l/s and l/l subjects. Independent of genotype, PR infants also exhibited higher rates of anxiety-like ventral clinging and self-directed behaviors, as well as sitting in close proximity. During a social separation stressor, serotonin transporter gene variation resulted in higher rates of self-directed behaviors among PR animals, even though this relationship was not present at baseline or at the end of the separation paradigm. This finding suggests an increased sensitivity to acute stress conferred by the l/s genotype among PR macaques. Interestingly, as these monkeys age, when gender is considered in our analyses, there is a sex by serotonin transporter genotype interaction, such that males with the l/s genotype have higher composite scores for alcohol consumption and alcohol-induced aggression. Over the past year, the effort to find functional polymorphisms in important neuropsychiatric candidate genes in our rhesus animals has been taking on an increasingly vital role in our research goals. As part of our ongoing collaboration with Dr. Klaus-Peter Lesch (of the University of Wuerburg, Germany) we have been analyzing genotypes from a monoamine oxidase genetic variant (MAOA) and their relationship to some the behavioral phenotypes from our lab. In parallel with the recent paper in the journal Science by Caspi et al, (in which there was a strong correlation with a low activity variant of the MAOA gene and males with conduct disorder that had experienced childhood abuse) we found that rates of competitive aggression were higher in MR males with the low activity allele. Dr. Newman recently investigated the hypothesis that variation in MAOA genotypes in males would be correlated with variation in alcohol consumption. He found that one of the three alleles present in macaques conferring reduced transcriptional activity was strongly correlated with decreased alcohol consumption, but only in MR males. Thus, as with the previously described study, there is a clear gene by environment interaction. In this case, the low activity allele may provide a mild buffering effect against the stress of PRing. In a collaboration with Lars Oreland of Uppsala University, in Sweden, we initiated studies of the MAO-B genotypes that he has indentified in humans. To date, polymorphic genotypes that are found in the human, such as the AP2 beta gene located in the intron have not been found in the macaque. Dr. Newman has also characterized a genetic variant found in humans in COMT. This variant is present in humans with a number of psychiatric and other medical disorders. While the COMT gene fragment that contains the val158met polymorphism amplified, it appears that the human polymorphism is not present in macaques. To further develop this investigation, he is currently sequencing the two promoter regions of the COMT gene. Dr. Christina Barr has sequenced the promoter region of the CRH gene, finding it to be polymorphic among our study animals. It is yet to be evaluated in relation to LHPA-axis function or behavioral phenotypes.